Respiratory and Ocular Toxicity of Inhaled Nanomaterials

吸入纳米材料的呼吸和眼毒性

• 批准号: 9770859
• 负责人: KENT Ed PINKERTON
• 金额: $ 43.5万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770859
• 关键词: 3-Dimensional; Aerosols; Affect; Air; Autopsy; Biological; Caliber; California; Carbon; Carbon Nanotubes; Cell Line; Cells; Characteristics; Charge; Cornea; Corneal Injury; Coupled; Deposition; Engineering; Epithelium; Exposure to; Extracellular Matrix; Eye; Eye Injuries; Gene Proteins; Goals; Health; Histologic; Human; In Vitro; Inflammation; Inflammatory; Inhalation; Injury; Laboratories; Liquid substance; Lung; Macaca mulatta; Measures; Mediating; Metals; Methods; Microdissection; Microscopic; Modeling; Molecular; Monkeys; Nebulizer; Ophthalmology; Organ; Organism; Pattern; Physicians; Physiological; Population; Positioning Attribute; Powder dose form; Primates; Process; Property; Publications; Rattus; Research; Research Personnel; Resources; Respiratory System; Retina; Risk; Role; Shapes; Signal Transduction; Site; System; Testing; Therapeutic; Tissues; Toxic effect; Wound Healing; aerosolized; base; body system; cell type; cost; cytotoxicity; experience; exposure route; in vivo; in vivo evaluation; injury and repair; innovation; interest; macrophage; metal oxide; nanomaterials; nonhuman primate; novel; novel strategies; ozone exposure; particle; physiologic model; recruit; respiratory; response; retinal imaging; surface coating; wound

SUMMARY We hypothesize differences in composition, size, diameter and surface coating of engineered nanomaterials (ENM) will modulate the in vivo deposition, distribution and biologic effects of aerosolized ENM to the lungs and the eyes. In this project, we will systematically test diverse ENM following aerosolization to identify the key characteristics that influence their toxicity. We have chosen to examine health effects in the respiratory tract and the eye, since both organ systems represent the major route of exposure to aerosolized ENM. Our focus will be to create real and relevant exposure scenarios by inhalation to the major classes of ENMs, a common and expected route of exposure. Further, the lungs and the eyes are both current targets of ENM-based therapeutic delivery. Our goal in this proposal is to systematically and quantitatively compare the health effects of nanomaterials with different physicochemical properties on these organ systems using physiologically relevant models. The health effects will include detailed molecular and pathophysiologic changes that will be targeted to zones of ENM deposition and retention. We are well positioned to contribute to the new NHIR consortium efforts on ENM. We have experience working with many of the materials listed. Because a potentially large number of materials will be systematically tested, a tiered paradigm with clear indications for which ENM need in vivo testing will be used. We have a strong publication record of ENM health effects research in vivo and ex vivo, particularly of novel material aerosols including laboratory generated, dry powder and nebulized liquid aerosols. Our team has expertise in metals, metal oxides, carbon particles, carbon nanotubes and 3-dimensional ENM Coupled with this are the novel methods developed in the Van Winkle, Thomasy and Pinkerton laboratories to study site-specific cellular responses and well-characterized methods in corneal and retinal imaging commonly used in physician-based ophthalmology. These novel approaches include microscopic and histologic approaches to localize ENM in tissues as well as the application of microdissection to study ENM retention and site specific gene, protein and cellular responses. Further, all three investigators have the ability to take advantage of a unique resource, the California National Primate Research Center This enables in vitro studies of ENM effects in a model physiologically relevant to humans, nonhuman primate explants and cells. We know that cell lines give divergent results and so the proposed studies in this application will emphasize primary cells or tissue explants for our organs of interest, coupled with in vivo studies of select ENM aerosols as defined by the consortium. The specific aims of our proposal provide novel and innovative methods to measure cell-based cytotoxicity, inflammation and remodeling in both normal and injury repair models of the complete respiratory tract, as well as the cornea and retina.

概括 我们假设工程纳米材料的组成，大小，直径和表面涂层的差异 （ENM）将调节雾化ENM对肺的体内沉积，分布和生物学作用 和眼睛。在这个项目中，我们将系统地测试雾化后的不同ENM，以识别关键 影响其毒性的特征。我们选择检查呼吸道中的健康影响 和眼睛，因为这两个器官系统代表了暴露于雾化的ENM的主要途径。我们的重点 将通过吸入主要类ENM来创建真实和相关的暴露场景，这是常见的 和预期的曝光途径。此外，肺和眼睛都是基于ENM的当前目标 治疗性分娩。我们在此提案中的目标是系统地和定量地比较健康效应 使用生理上的这些器官系统上具有不同物理化学特性的纳米材料的纳米材料 相关模型。健康影响将包括详细的分子和病​​理生理学变化 针对ENM沉积和保留区域。我们有能力为新的NHIR做出贡献 财团对ENM的努力。我们有与列出的许多材料一起工作的经验。因为 潜在的大量材料将进行系统测试，一个分层范式，有明确的指示 将使用哪些ENM需要体内测试。我们对ENM健康效应有很强的出版记录 研究体内和体内研究，特别是针对新型材料气溶胶，包括实验室生成的干粉 和雾化的液体气溶胶。我们的团队在金属，金属氧化物，碳颗粒，碳方面具有专业知识 纳米管和三维ENM与此相结合是范·温克尔（Van Winkle）开发的新方法， Thomasy和Pinkerton实验室研究特定地点的细胞反应和特征良好的方法 在基于医师的眼科中常用的角膜和视网膜成像中。这些新颖的方法 包括微观和组织学方法，以将ENM定位在组织中以及应用 微分解以研究ENM保留和特定基因，蛋白质和细胞反应。此外，这三个 调查人员有能力利用独特的资源，加利福尼亚国家灵长类动物研究 中心这可以在与人类，非人类相关的模型中对ENM效应进行体外研究 灵长类动物外植体和细胞。我们知道细胞系带来不同的结果，因此在此中提出的研究 应用将强调我们感兴趣的器官的原代细胞或组织外植体，并加上体内 财团定义的精选ENM气溶胶的研究。我们提案的具体目的提供了小说 以及在正常和 全呼吸道以及角膜和视网膜的损伤修复模型。